Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1.
Efavirenz is chemically, (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2, 4-dihydro-1H-3, 1-benzoxazin-2-one also used in combination with other antiretroviral agents as part of an expanded post exposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk.
WO Patent Application Publication No. WO 2006/018853 discloses the synthesis of crystalline and amorphous form of efavirenz i.e. crystalline efavirenz form H1 and is characterized by an x-ray powder diffraction spectrum having peaks expressed as 29 at about 5.4, 10.4, 11.6, 12.5, 15.3, 20.1, 20.8, 22.5, 23.1, 25.7, 27.9, 28.5, 28.8, 29.5, 30.2 and 38.2 degrees.
As the form is new, the characteristics as well as its behavior in vivo are not known. Tablets were made using the conventional methods and conducted bioequivalence study and found that it is not bioequivalent to the RLD.
It is known that the degree of solubility can influence the bioavailability, attempts were made to increase the solubility using various techniques known in the prior art such as ultrasonication, particle coating and particle size reduction.
Ultrasonication was not successful in enhancing the solubility and retaining the characteristics of new polymorph of efavirenz.
Particle coating showed an improvement in retaining the characteristics of new polymorph but no change was observed in terms of solubility.
With the earlier expertise in developing the formulation of efavirenz, it has been found that there is a requirement of special particle size to increase the solubility in order to achieve the desired bioavailability and to make a formulation bioequivalent to the reference listed drug.
Different techniques were evaluated to reduce the particle size of efavirenz such as impact milling, fluid energy milling, wet milling and tumbling by ball mill.
Impact milling, fluid energy milling and tumbling by ball mill were failed to retain the characteristics of novel form. When the wet milling process developed by the inventor was applied to achieve particle size reduction, it has been found that there is no conversion of one form to another form of efavirenz.
The polymorph used in the process of size reduction by the process of invention is preferably efavirenz form H1.
Tablets and capsules were made with the obtained efavirenz after wet milling using pharmaceutically acceptable excipients like super disintegrant viz. crospovidone and sodium starch glycolate, diluent/filler viz. microcrystalline cellulose and lactose, glidant viz. talc, colloidal silicon dioxide, sodium benzoate and magnesium oxide, lubricant viz. magnesium stearate, zinc stearate, calcium stearate, sodium lauryl sulfate and sodium stearyl fumarate.
The tablets and capsules were submitted to bioequivalence study and found that these are bioequivalent with reference listed drug.